On a worldwide basis, malaria is one of the most common infectious diseases. Even though it has been largely eliminated from North America and Europe, it remains the most serious infectious disease in tropical and subtropical regions of the world. According to the World Health Organisation, WHO, there are about 100 million new cases each year, and about 300 million people in the developing countries exhibits chronical malaria infections. Malaria is caused by four species of Plasmodium, of which Plasmodium vivax and Plasmodium falciparum are most frequently involved in human infections. The vector responsible for transmitting malaria to humans is the Anopheles mosquito and only malaria infections caused by Plasmodium falciparum may be fatal to humans.
After inoculation in the body, the sporozoites of Plasmodium begin to reproduce within liver cells. Multiplication of Plasmodium sporozoites occurs by schizogony, in which a single sporozoite can produce as many as 40,000 merozoites. The invasion of erythrocytes by hepatic merozoites begins the erythrocytic phase of malaria, causing fever and other severe manifestations.
Erythrocytes infected with the malaria parasite P. falciparum disappear from the peripheral circulation as they mature from the ring stage to trophozoites. This phenomenon is known as sequestration and results from parasitized erythrocyte adherence to microvascular endothelial cells and erythrocytes in diverse organs. Severe Plasmodium falciparum-malaria is characterized by excessive sequestration of infected- and uninfected erythrocytes in the microvasculature of the affected organ.
Thus, Plasmodium falciparum is an intracellular protozoan, which during its vertebrate life cycle invades and multiplies in liver and red blood cells. The virulence of the parasite is associated with the capacity of the infected erythrocyte to adhere to endothelial cells and to erythrocytes, so called resetting. This may cause impaired local oxygen delivery and thereby death of the human host (Miller, L. H., F. Good, and G. Milon. 1994. Malaria pathogenesis. Science 264, 1878–1883, Pasloske, B. L. and R. J. Howard. 1994. Malaria, the red cell, and the endothelium. Ann. Rev. Med. 45, 283–295, Marsh, K., M. English, J. Crawley, and N. Peshu, 1996. The pathogenesis of severe malaria in African children. Ann. Trop. Med, & Parasitol. 90, 395–402). The most malignant form of the infection is cerebral malaria, due to a massive sequestration of infected and uninfected erythrocytes in the brain micro-vasculature.
After being transported from the internal parasite, antigens involved in the binding of cells are thought to be concentrated and subsequently exposed to the exterior of the erythrocyte at minute (≈100 nm in diameter), electron-dense excrescence's called knobs (Atkinson, C. T. and M. Aikawa, 1990. Ultrastructure of malaria-infected erythrocytes. Blood Cells 16, 351–368). One such antigen is Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1), a polypeptide of 200–350 kDa encoded by the var family of P. falciparum genes (Howard, R. J., J. W. Barnwell, and V. Kao, 1983. Antigenic variation in Plasmodium knowlesi malaria: identification of the variant antigen on infected erythrocytes. Proc. Natl. Acad. Sci. U.S.A. 80, 41294133, Su, X. -Z, V. M. Heatwole, S. P. Wertheimer, F. Guinet, J. A. Herrfeldt, D. S. Peterson, J. A. Ravetch, and T. E. Wellems. 1995. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 82, 89–100, Baruch, D. I., B. L. Pasloske, H. B. Singh, X. Bi, X. C. Ma, M. Feldman, T. F. Taraschi, and R. J. Howard. 1995. Cloning th P. falciparum gene encoding PfEMP1, a malaria variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82, 77–87). The feature of antigenic variation and switching of the surface of the pRBC has been attributed to the var-genes. Even though up to 150 such genes are harboured in the genome, only one PfEMP1 is thought to be expressed at any one time. PfEMP1 has features of an adhesive molecule and has been associated with the cytoadherent properties of the infected red cell (Smith, J. D., C. E. Chitnis, A. G. Craig, D. J. Roberts, D. E. Hudson-Taylor, D. S. Peterson, R. Pinches, C. I. Newbold, and L. H, Miller. 1995. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82, 101–110, Baruch, D. I., J. A. Gormley, C. Ma, R. J. Howard, and B. L. Pasloske. 1996. Plasmodium falciparum erythrocyte membrane protein 1 is a parasitised erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1. Proc. Natl. Acad. Sci. U.S.A. 93, 3497–3502). For example, the expression of PfEMP1-encoding var genes has been shown to correlate with the capacity of the pRBC for binding to host receptors, including CD36 and ICAM-1 (Baruch, D. I., J. A. Gormley, C. Ma, R. J. Howard, and B. L. Pasloske. 1996. Plasmodium falciparum erythrocyte membrane protein 1 is a parasitised erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1. Proc. Natl. Acad. Sci. U.S.A. 93, 3497–3502, Gardner, J. P., R. A. Pinches, D. J. Roberts, and C. I. Newbold, (1996). Variant antigens and endothelial receptor adhesion in Plasmodium falciparum. Proc. Natl. Acad. Sci. U.S.A., 93, 3503–3508). A role for PfEMP1 in resetting was recently suggested by Rowe et al (Rowe, J. A., J. M. Moulds, C. I. Newbold, and L. H. Miller. 1997. P. falciparum resetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1. Nature 388:292–295). Complement receptor 1 was found to be the host-receptor. However, it is beleived that it cannot be the only one used by rosetting parasites.
In WO 96/33736, one PfEMP1 variant is disclosed by sequence. However, this is only one of several possibly existing variants, all of which are different as to functional sequences as well as adhesive properties.
Accordingly, due to the complex nature and/or mechanism of malarial antigenic variation and the virulence thereof, there is still a great need for methods and compositions which may be useful in the treatment, diagnosis and prevention of malaria infections.